1. Field of the Invention
The present invention relates to the pulmonary hemodynamics of the equine. More particularly, this invention is directed to the use of type V phosphodiesterase inhibitors (PDIs) to reduce pulmonary capillary stress failure and, consequently, attenuation of exercise induced pulmonary hemorrhage (EIPH) in performance horses.
2. Prior Art
Horses experiencing EIPH, also known as “bleeders,” represent a serious problem to the horse racing industry. Studies of horses in training and those in competition at racetracks have shown that from about 70% to 100% of them experience EIPH after performing. This has been shown both endoscopically (Pascoe et al. 1981; Sweeney, 1991) and from trans-tracheal washings (Whitwell and Greet, 1984). Horses that bleed heavily may have a reduced athletic performance and/or a shortened athletic career and thus EIPH is one of the most serious veterinary problems facing the horse racing industry.
Although numerous hypotheses have been proffered, it is generally accepted by the scientific community that pulmonary capillary stress failure is the casual determinant of exercise induced pulmonary hemorrhaging in performance horses. The rational is based on studies by M. Manohar (Am J. Vet. Res, 1993, 54:142-146) and West et al. (J. Appl. Physiol., 1991, 71:573-582 and J. Appl. Physiol 1993, 75: 1097-1109) among others who have demonstrated that excessive pulmonary artery pressure and stress failure at the pulmonary capillary level is due to increased transmural pressure during strenuous exercise of the equine. Further, it is known that horses have a relatively thin pulmonary blood-gas barrier to facilitate oxygen uptake during high intensity exercise. During exercise, pulmonary blood flow increases by as much as eight fold to satisfy the oxygen requirements of the horse. Basal compensatory mechanisms in mammals other than horses include functional recruitment of the pulmonary capillary bed.
Mills et al. (Br. Vet. J., 1996, 1952:119-122) studied the synthesis of nitric oxide (NO) in horses subjected to high speed treadmill tests by introducing N-nitro-L-arginine methyl ester (L-Name) directly into the pulmonary artery. This compound has been shown to inhibit the in situ production of NO, which is known to regulate resting pulmonary vascular tone in many species. During exercise a reduced level of NO in the lungs resulted in a significant increase in the pulmonary artery pressure. Conversely, the introduction of L-arginine, a structural analog of L-Name, into the pulmonary artery of exercising horses was shown by West et al. to reverse the restricted production of NO with a subsequent beneficial decrease in pulmonary artery pressure.
Even though the administration of L-arginine improves the production of NO in the lungs of equine and, consequently, results in less bleeding, there is still a need to further decrease pulmonary artery pressure during strenuous exercise of the equine. The present invention fulfills this need by the use of type V phosphodiesterase inhibitors as a novel independent therapeutic modality in the treatment of exercise induced pulmonary hemorrhage in equine.